50 Years Later, Symptoms of Inflammation During Pregnancy are Linked to Aging and Memory Changes

In a new study, data from participants who had been followed for over 50 years, i.e. since birth, were analyzed. The researchers found that maternal immune activity during a critical period of sex-dependent brain development in utero influenced the long-term memory circuits and function of the offspring in childhood and middle age, with different patterns in males and females.

It is estimated that by 2050, Alzheimer’s disease will affect approximately 150 million people worldwide, including 17 million in Europe. It is well known that the brain circuits underlying memory differ depending on biological sex, but the sex-specific factors for aging and Alzheimer’s disease are still unclear. A new study by researchers at Mass General Brigham analyzed data from participants who had been observed for over 50 years, starting before they were born. The researchers found that maternal immune activity during a critical period of sex-dependent brain development in utero influenced the long-term memory circuits and function of offspring in childhood and middle age, with different patterns in males and females. The results were published in Molecular Psychiatry.

How Maternal Immune Activity and Offspring Brain Development are Linked

“Brain aging is also about brain development, and understanding sex differences in brain development is critical to understanding sex differences in the aging brain,” said corresponding author Jill M. Goldstein, PhD, MPH, founder and executive director of the Innovation Center on Sex Differences in Medicine at Massachusetts General Hospital, a founding member of the Mass General Brigham Health System, and professor of psychiatry and medicine at Harvard Medical School. This work is a first step, the researchers say, in examining the fetal origins of Alzheimer’s disease, which, like many chronic diseases, develops over a lifetime and is affected by early development in ways we don’t usually consider.

This study was based on the findings of a cohort formed over 60 years ago, which includes the adult offspring of nearly 18,000 pregnancies between 1959 and 1966, observed as part of the New England Family Study (NEFS). The current research included 204 individuals who were born during the study and were or were not exposed to an unfavorable immune environment in utero (i.e., elevated levels of immune markers such as the cytokines IL-6 and TNF-a), and were followed up 50 years later in midlife. The team used functional imaging to examine the effects of this early exposure on brain regions in the memory circuit that are rich in these cytokine and sex hormone receptors and exhibit sex differences in development and functioning that begin as early as fetal development.

The researchers found that elevated maternal levels of IL-6 and TNF-a during pregnancy were associated with sex differences in adverse brain activity in the memory circuits of the offspring later in life, particularly in postmenopausal women. These women also had higher markers of a pro-inflammatory state at midlife. Furthermore, the researchers found evidence of the effects of these immune markers even earlier, on the cognitive performance of children at the age of seven, underscoring the link between stress during pregnancy and brain health in later life. Their findings suggest that increased maternal prenatal immune activity may contribute to the development of increased immune and stress sensitivity in offspring, leading the researchers to hypothesize that these offspring may be predisposed to gender-specific memory disorders such as Alzheimer’s disease later in life.

Further Research Needed

The researchers are continuing to follow the participants as they age to examine amyloid levels and other measures of Alzheimer’s-related pathology and further explore the link between prenatal immunity and Alzheimer’s disease. Current goals include understanding the mechanisms by which maternal immune activity affects fetal brain development, identifying biomarkers of future memory impairment in early midlife, and understanding how other developmental periods, such as adolescence, affect the aging brain.

“While prenatal immune activity can influence offspring brain development, that doesn’t mean pregnancy is deterministic,” Goldstein says. Of course, later environmental exposures are critical, just as the womb environment is important. Fortunately, the brain is exceptionally adaptable, and researchers are seeking to understand the cognitive, behavioral, and sex-related factors associated with risk and resilience so that they can intervene early and maintain intact memory function in old age.